CS264902B1 - Process for preparing 5'-deoxy-5-fluorouridine - Google Patents

Abstract

A method for preparing 5-deoxy-5-fluorouridine, consisting in treating 5-deoxyuridine, especially its diacetyl derivative, with fluorine in acetic acid, and the resulting 6-acetoxy-2',3'-di-O- -acetyl-5"-deoxy-5-fluoro-5,6-dihydrouridine is isolated and converted to 5'-deoxy-5-fluorouridine with methanolic sodium methoxide. The resulting product has a cancerostatic effect.

Description

The present invention provides a process for the preparation of 5'-deoxy-5-fluorouridine, a biologically active substance having a high cancerostatic effect.

The substance prepared according to the present invention is currently of particular interest because it exhibits higher efficacy and lower toxicity in in vitro experiments than the parent compound 5-fluorouracil, which is widely used in cancer chemotherapy. The substance is therefore referred to as a prodrug of 5-fluorouracil (J. Med. Che. 25, 1034, 1982, Cancer Research 43, 2 525, 1983). Attention was therefore paid to the development of methods of preparation that could find technical application. None of these routes, however, utilize direct fluorination (Helv. Chim. Acta 65, 1522, 1982, J. Med. Chem. 25, 999 (1982)),

The fluorination method is an object of the invention. The process of the present invention is a substantial economic improvement over the prior art processes and provides a realistic prerequisite for the economically advantageous preparation of this cytostatic. Its main advantage lies in the fact that all intermediate synthesis steps are carried out with non-fluorinated nucleoside derivatives and the conversion to the desired 5-fluorouracil derivative is carried out de facto in one reaction step at the end of the synthesis. This minimizes economically demanding operations with fluorinated derivatives. 5'-Deoxyuridine, as a starting material for the synthesis of 5 ^- deoxy-5-fluorouridine, is prepared according to the author's certificate No. 199 949, 204 212 to 204 214. Another advantage of the process according to the invention is the simple carrying out of the reaction conventional chemical laboratory equipment including an efficient fume hood and does not require special equipment. Another advantage is the high yield of 5'-deoxy-5-.

-fluoruridine calculated on the starting 5‘-deoxyuridine, possibly uridine. The process is a substantial economic advantage over previously known syntheses.

The present invention is based on the method of the present invention. 5'-deoxy-5-fluorouridine, characterized in that 5-deoxyuridine, in particular its diacetyl derivative, is converted to 5'-deoxy-5-fluorouridine by treatment with fluorine in a solution of acetic acid and subsequent action of methanolic sodium methoxide.

Further, the individual reaction steps may be separated and the reaction intermediates isolated. After completion of the fluorination reaction, the product is isolated by shaking between organic solvent and water, and possibly subsequent silica gel chromatography (or high performance liquid chromatography) to give 6-acetoxy-2 ', 3'-di-O-acetyl-5-fluoro- 5,6-dihydrouridine, which can be crystallized from 2-propanol. The dihydroderivative can be converted to diacetyl-5-deoxy-5-fluorouridine by treatment with an organic base in an organic solvent, preferably triethylamine in ethanol, or by heating or sublimation, and can be converted to 5 1-deoxy-5-fluorouridine. The product of the fluorination reaction by the action of an inorganic base, preferably sodium carbonate, is converted to 5'-deoxy-5-fluorouridine.

The nucleoside fluorination can also be performed in another organic solvent, e.g., propionic acid, chloroform, fluorinated solvents. Instead of a methanolic solution of sodium methoxide, a solution of another alkali metal alkoxide in the corresponding alcohol may be used. Another non-water-miscible organic solvent may be used to isolate the dihydrouracil derivative and a dilute acidic carbonate solution may be used instead of water for shaking.

Other organic bases may be used in place of triethylamine to convert the dihydrouracil derivative to the 5-fluorouracil derivative. A wide range of inorganic bases, alkali carbonates, alkali hydroxides, basic ion exchangers, ammonia can be used to treat any of the intermediate steps to give the final 5'-deoxy-5-fluorouridine instead of methanolic sodium methoxide. The chromatography of all intermediates as well as the end product can advantageously be performed by high performance liquid chromatography.

The process of the present invention is generally applicable to the fluorination of pyrimidine nucleosides and analogues thereof, particularly uridine and 2'-deoxyuridine.

In the following, the invention is explained in more detail in the examples without being limited thereto.

CS 264 902 Bl

Example 1

To a solution of 2,3-di-O-acetyl-5-deoxyuridine (1.56 g) in acetic acid (200 mL) was added, under stirring and external cooling, nitrogen gas diluted with nitrogen (1: 5) until the starting material disappeared ( about 20 h) (monitored by silica gel thin layer chromatography). The reaction solution was then sparged with nitrogen (30 min), evaporated in vacuo and codistilled twice with acetic acid and 2x with ethanol. The residue was dissolved in ethyl acetate (200 mL) and shaken 3x with 5% sodium bicarbonate solution and 1x with water. The ethyl acetate solution was dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in 0.15 M sodium methoxide (40 mL) and left at room temperature (12 h). The solution was neutralized with an acidic ion exchanger in the H @ ⁺ -cycle (Dowex 50 H @ ⁺ ), the ion exchanger was filtered off, washed with methanol and evaporated in vacuo. The residue was crystallized from 2-propanol. A total of 960 mg (78%) of 5-deoxy-5-fluorouridine was obtained, m.p.

Mp 186-188 ° C.

Example 2

To a solution of 2 ', 3-di-O-acetyl-5'-deoxyuridine (1.4 g) in 50 ml of acetic acid (distilled from ^P 2 ° 5?) ^Is added a previously prepared solution of fluorine (6 mM) in The solution was bubbled with nitrogen (30 min) and evaporated in vacuo, the residue was codistilled twice with acetic acid and 2x with ethanol and dissolved in ethyl acetate (200 mL). The mixture was shaken with water (6x20 ml) to remove the acidic reaction of the shaking water and evaporated in vacuo to give 1.45 g (98%) of a residue, chromatographically uniform, whose analysis and NMR were consistent with 6-acetoxy-2 ', 3-di -O-Acetyl-5-fluoro-5,6-dihydrouridine Crystallization from 2-propanol gave a crystalline form of this material.

The residue further treated as in Example 1 gave a total of 894 mg (81%) of 5'-deoxy-5-fluorouridine, m.p. Mp 186-188 ° C.

Example 3

Fluorination of 2 ', 3'-di-O-acetyl-5'-deoxyuridine (3.12 g) was carried out as described in Example 1. The 6-acetoxy-diacetyl-5-deoxy-5-fluoro-5,6-dihydrouridine was obtained. Dissolve in 99% ethanol and after triethylamine is added to the alkaline reaction, the solution is left at room temperature (24 h). After evaporation in vacuo, the residue obtained was dissolved in ethyl acetate (200 ml) and shaken with water (3 x 20 ml). The residue of the ethyl acetate solution is chromatographed on silica gel with ethyl acetate-toluene (1: 1). 2.345 g (71%) of 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluorouridine are obtained with corresponding analysis and MNR spectrum. By saponification of the acetyl groups by a conventional procedure, e.g. as described in Example 1, 5-deoxy-5-fluorouridine (1.58 g, 64%) is obtained, m.p. Mp 186-188 ° C.

Example 4

A solution of diacetyl-5'-deoxyuridine (1.56 g) in acetic acid was fluorinated as described in Example 1. The obtained 6-acetoxy-2 ', 3'-di-O-acetyl-5'-deoxy-5-fluoro- 5,6-Dihydrouridine is converted to 2 ', 3'-di-O-acetyl-5'-deoxy-5-fluorouridine by heating (possibly by sublimation in vacuo). Removal of the acetyl groups by a conventional procedure, e.g. according to Example 1, affords 5-deoxy-5-fluorouridine (1.97 g, 80%), m.p. Mp 186-188 ° C.

Example 5

A solution of diacetyl 5'-deoxyuridine (3.12 g) in acetic acid (dried Ρ ₂ ° ₅ , ²⁰⁰ π · ¹ ) is saturated with fluorine gas as described in Example 1. The 5-fluoro-5,6-dihydroderivative residue is dissolved in ethyl acetate (200 mL) and the solution was shaken vigorously (vibration mixer) with 10% sodium carbonate solution until all nucleoside derivative was transferred from the ethyl acetate solution to the aqueous phase. The aqueous phase is neutralized with an acidic ion exchanger in an H ⁺ cycle. The ion exchanger is filtered off with suction and washed and the filtrate is evaporated in vacuo. 1.77 g (72%) of 5'-deoxy-5-fluorouridine are obtained, mp 186-188 ° C.

Claims (1)

BEFORE YOUR INVENTION Process for the preparation of 5'-deoxy-5-fluorouridine characterized in that 5'-deoxyuridine, in particular its diacetylderivative, is treated with fluorine in acetic acid, and the resulting 6-acetoxy-2 ', 3'-di-O-acetyl-5 is formed. The 5'-deoxy-5-fluoro-5,6-dihydrouridine was isolated and converted into 5'-deoxy-5-fluorouridine by methanolic sodium methoxide.